The Dark Side of "Good" Cholesterol

The HDL Cholesterol Story Is More Complicated Than We Thought

HDL Cholesteral
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For many years, HDL cholesterol has been widely known as “good cholesterol,” because higher blood levels of HDL cholesterol have been strongly associated with a reduced risk of atherosclerosis and cardiac disease. Cardiologists (including this one) have long urged their patients to make lifestyle choices that raise their HDL cholesterol, and researchers have worked hard to invent easier ways to increase HDL levels (that is, with drugs).

  And to this day the popular press still refers to HDL cholesterol largely as being unremittingly “good.”

But for at least a few years now, researchers have known that the HDL story is a lot more complicated than everyone had hoped.  In fact, it is now clear that HDL cholesterol is not always good for the cardiovascular system. 

When Is "Good" Cholesterol Not Good?

The first strong clue came from clinical trials conducted a few years ago with a new class of drugs (the so-called CETP-inhibitors) that reliably raise HDL cholesterol levels. One of these drugs — torcetrapib (from Pfizer) — resulted in increased cardiovascular risk despite the fact that it significantly increased HDL levels. Another study involving a second CETP-inhibitor — dalcetrapib (from Roche) — was halted because there was no sign that it was improving cardiac risk, again despite an increase in HDL. Perhaps especially disappointing was the publication of the AIM_HIGH study in 2011, which assessed the effectiveness of raising HDL levels with niacin (a drug commonly used in clinical practice for this purpose).

  Not only was there no reduction in cardiovascular benefit among patients receiving niacin, but also they had an increased risk of stroke.

And so, recent clinical trials have shown at the very least that an increase in HDL cholesterol - at least when that increase is induced by drugs - is not universally a good thing, and sometimes may even be bad.

  The simple formula, “HDL cholesterol = good cholesterol” is in need of serious revision.  A new hypothesis about HDL cholesterol is required.

A New Type of Misbehaving HDL Cholesterol

In early 2014, a report from researchers at the Cleveland Clinic added another piece to the HDL puzzle. They discovered a new form of HDL, in which part of the HDL complex (specifically, the portion of the apolipoprotein A1, which constitutes the majority of the HDL particle), becomes abnormally oxidized. This oxidation apparently takes place within atherosclerotic plaques, when the HDL particles arrive there to carry away excess cholesterol. The new, oxidized species of HDL no longer functions as HDL. That is, it no longer carries cholesterol away from the blood vessel wall. Instead, it mostly remains within the plaque, and stimulates inflammation there. (This is in stark contrast to “normal” HDL, which displays anti-inflammatory properties.) In other words, the oxidized HDL is converted from a particle that reduces atherosclerosis into one that stimulates atherosclerosis.

Tiny amounts of this oxidized HDL may leach out of the plaques, and then can be measured in the bloodstream. The Cleveland Clinic investigators found that blood levels of this abnormal HDL correlated with an increase in cardiovascular risk.  (Measuring the oxidized HDL species is a research tool available in only a few institutions.)

What Does All This Mean To Us Folks?

Despite the growing complexity of the “HDL cholesterol story,” none of this should really be very confounding to you and your doctor. In fact, how you should look at HDL cholesterol, and what you should do about it, are really pretty simple.

  1. Higher HDL levels, at least when they are induced naturally and not by drugs, are still a good thing, and strongly correlate with reduced cardiovascular risk.
  2. Lifestyle modifications that increase HDL levels are very desirable, and because of their overall effect on cardiovascular health ought to be adopted regardless of their effect on your HDL levels. These include aerobic exercise, not smoking, maintaining a normal weight, avoiding trans fatty acids, consuming monounsaturated fatty acids (as found in olive oil, avocados, and canola oil), and (dare he say it?) consuming small amounts of alcohol. Read how to increase your HDL levels safely.
  3. A more thorough understanding of HDL cholesterol metabolism is needed before medical science subjects lots of people to any more new drugs that increase HDL cholesterol levels. Clearly, not all HDL cholesterol can be considered good, and researchers ought to be pretty sure they’re increasing the good stuff before they ask us to swallow whatever turns out to be their idea of the next big thing.

Sources:

Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 2014; published online December 26, 2014. DOI:10.1038/nm.3459.

Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med 1991; 325:461.

Moffatt RJ. Effects of cessation of smoking on serum lipids and high density lipoprotein-cholesterol. Atherosclerosis 1988; 74:85.

Gerasimova E, Perova N, Ozerova I, et al. The effect of dietary n-3 polyunsaturated fatty acids on HDL cholesterol in Chukot residents vs muscovites. Lipids 1991; 26:261.

The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255-2267 DOI: 10.1056/NEJMoa1107579

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